The overall objective of this proposal is to define the mechanisms of regulation of cerebral blood flow (CBF) and metabolism under a variety of unusual circumstances. One major aim of this proposal will be to integrate the activities of various disciplines in such a way that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. Several factors (the nervous system, chemical and metabolic, pharmacologic and mechanical) exert significant control over the cerebral vasculature under a variety of physiologic and pathophysiologic conditions. The projects outlined in this proposal attempt to clarify some of the mechanisms by which these regulatory factors work in a variety of conditions. In Project I, the potential role of 02 derived free radicals on CBF and metabolism in reversible focal cerebral ischemia will be examined. In Project II, we will investigate the dynamics of the mechanisms causing metabolic and physiologic abnormalities following complete and incomplete global cerebral ischemia. These two projects will correlate the rate of return of cerebral function, metabolism and CBF following ischemia (focal, global, complete or incomplete). Project III examines mechanisms of how interventions made during cardiopulmonary resuscitation (CPR) effect cerebral perfusion, metabolism and function during CPR and following cardiac resuscitation in an adult and infant model of CPR. Project IV examines the regulation of CBF and metabolism in the fetus and newborn with specific reference to hypoxia. The regulation of hypophyseal blood flow and its relationship to neurohypophyseal hormonal release will be examined in Project V. Finally, Project VI will investigate mechanisms of physiological vascular abnormalities in hyperammonemia. The multidisciplinary approach of the investigators and their different expertise permits novel and innovative approaches to questions concerning the regulation of CBF in health and disease.